Some eight million children and teenagers across the Southeast Asian nation will receive the shot to prevent further spread of the disease which is caused by a bacterial infection.
It can lead to breathing difficulties, heart failure, paralysis, and even death if left untreated.
Widespread incidents of the communicable disease are relatively rare in Indonesia, although it had the second largest number of reported cases globally from 2011-2015, behind India, according to the World Health Organization.
The vaccination programme started from Monday in three of the country's most populous provinces, including the capital Jakarta, and could continue into next month, officials said.
The spike in cases is due to poor public awareness as well as a growing anti-vaccination movement in Indonesia, the health ministry said.
"Diphtheria cases have been rare for a long time in Indonesia, so people were no longer aware of the danger and did not take their children for vaccinations," senior ministry official Jane Soepardi told AFP.
"It was not scary at all. My teacher told me we all must be vaccinated and it did not hurt either," Ragil Setiawan, a 10-year-old student at an elementary school in Tangerang, just outside of Jakarta, said Monday after getting his shot.
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